Asialoglycoprotein receptor (ASGPR) is a transmembrane receptor composed of two subunits, H1 and H2. The subunits are believed to oligomerize through their extracellular stalk regions. ASGPR is a member of the C-type lectin family (calcium-ion dependent lectin) and mediates the endocytosis and degradation of a wide variety of desialylated glycoproteins. ASGPR is selectively expressed on liver parenchymal cells (hepatocytes), which makes it an attractive target for liver-specific therapies. Many liver diseases, e.g. hepatitis, liver cirrhosis or hepatocellular carcinoma (HCC), can be caused directly or indirectly by viral infection, such as hepatitis virus B (HBV) or C (HCV) infection. Chronic infection with HCV is one of the major causes of cirrhosis and HCC. Similarly, chronic HBV infection accounts for 5-10% of chronic liver disease and cirrhosis in the US. Approved therapies for HBV and HCV infection include interferons (IFN), such as interferon alpha. However, side effects have hampered development and widespread use of these therapies in many cases. Such IFN-associated side effects are thought to be due in part to induction of interferon-stimulated genes (ISGs) in peripheral blood cells following systemic exposure to IFN. Hence, to minimize side effects associated with IFN therapy for liver diseases, and also to augment the antiviral effect of conventional interferons, it is desirable to selectively deliver IFN to the liver. ASGPR has been recognized as potential target molecule on hepatocytes for such selective delivery. For example, WO 92/22310 describes an approach for targeting interferon to the liver by conjugation of recombinant IFN to an asialoglycoprotein. In a similar approach, an interferon molecule itself has been modified to produce asialo-interferon for binding to ASGPR (Eto and Takahashi, Nat Med 5, 577-581 (1999)) More recently, an approach based on anti-ASGPR single variable domain (dAb) antibodies has been described (WO 2011/086143).
However, none of these approaches has been shown to be clinically successful so far, and there remains a need for improved targeting molecules for selective delivery of therapeutic molecules, e.g. interferon, to the liver. The antibodies of the present invention combine several advantageous properties, which make them particularly suitable for targeting effector moieties such as interferons to ASGPR-expressing cells, e.g. for the treatment of liver diseases.